Obesity is recognized as a significant risk factor for Alzheimer's disease (AD). Studies have supported the notion that obesity accelerates AD-related pathophysiology in mouse models of AD. The majority of studies, to date, have focused on the use of early-onset AD models. Here, we evaluate the impact of genetic risk factors on late-onset AD (LOAD) in mice fed with a high fat/high sugar diet (HFD). We focused on three mouse models created through the IU/JAX/PITT MODEL-AD Center. These included a combined risk model with APOE4 and a variant in triggering receptor expressed on myeloid cells 2 (Trem2^R47H ). We have termed this model, LOAD1. Additional variants including the M28L variant in phospholipase C Gamma 2 (Plcg2^M28L ) and the 677C > T variant in methylenetetrahydrofolate reductase (Mthfr ^{677C >} ^T ) were engineered by CRISPR onto LOAD1 to generate LOAD1.Plcg2^M28L and LOAD1.Mthfr ^{677C >} ^T . At 2 months of age, animals were placed on an HFD that induces obesity or a control diet (CD), until 12 months of age. Throughout the study, blood was collected to assess the levels of cholesterol and glucose. Positron emission tomography/computed tomography (PET/CT) was completed prior to sacrifice to image for glucose utilization and brain perfusion. After the completion of the study, blood and brains were collected for analysis. As expected, animals fed a HFD, showed a significant increase in body weight compared to those fed a CD. Glucose increased as a function of HFD in females only with cholesterol increasing in both sexes. Interestingly, LOAD1.Plcg2^M28L demonstrated an increase in microglia density and alterations in regional brain glucose and perfusion on HFD. These changes were not observed in LOAD1 or LOAD1.Mthfr ^{677C >} ^T animals fed with HFD. Furthermore, LOAD1.Plcg2^M28L but not LOAD1.Mthfr ^{677C >} ^T or LOAD1 animals showed transcriptomics correlations with human AD modules. Our results show that HFD affects the brain in a genotype-specific manner. Further insight into this process may have significant implications for the development of lifestyle interventions for the treatment of AD.

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